Hemoglobin subunit delta (HBD) gene off-target locus (HBD)

The Hemoglobin subunit delta (HBD) gene encodes the delta-globin protein, which pairs with alpha-globin to form Hemoglobin A2 (HbA2), a minor component of adult hemoglobin (UniProt: P02042). While HBD is not typically a primary therapeutic target, it is a critical 'off-target' locus in the development of gene therapies for sickle cell disease and beta-thalassemia. Because the HBD gene shares high sequence homology with the Hemoglobin subunit beta (HBB) gene, CRISPR-Cas9 and other gene-editing tools designed to modify HBB may inadvertently bind to and cut the HBD locus (NCBI Gene: 3045). Such off-target activity can lead to unintended mutations, deletions, or chromosomal translocations between the HBB and HBD genes, which are located in close proximity on chromosome 11 (PubMed: 33283989). Consequently, the HBD locus is a primary focus of safety assessments and specificity profiling for genetic medicines targeting the beta-globin cluster.

Other names

Delta-globinHemoglobin delta chainHBDHBD locusHemoglobin subunit delta

The HBD locus acts as an unintended site for genomic cleavage or modification by gene-editing tools due to its high sequence homology with the HBB gene.